Blast-induced neurotrauma (BINT) is a prevalent brain injury within both military and civilian populations due to current engagement in overseas conflict and ongoing terrorist events worldwide. In the early 2000s, 78% of injuries were attributable to an explosive mechanism during overseas conflicts, which has led to increased incidences of BINT [1a]. Clinical manifestations of BINT include long-term psychological impairments, which are driven by the underlying cellular and molecular sequelae of the injury. Development of effective treatment strategies is limited by the lack of understanding on the cellular and molecular level [2a]. The overall hypothesis of this work is that epigenetic regulatory mechanisms contribute to the progression of the BINT pathology and neurological impairments. Epigenetic mechanisms, including DNA methylation and histone acetylation, are important processes by which cells coordinate neurological and cellular response to environmental stimuli. To date, the role of epigenetics in BINT remains largely unknown.
To test this hypothesis, an established rodent model of BINT was employed [3a]. Analysis of DNA methylation, which is involved in memory processes, showed decreased levels one week following injury, which was accompanied by decreased expression of the enzyme responsible for facilitating the addition of methyl groups to DNA. The one week time point also showed dramatic decreases in histone acetylation which correlated to decline in memory. This change was observed in astrocytes and may provide a mechanistic understanding for a hallmark characteristic of the injury. Treatment with a specific enzyme inhibitor was able to mitigate some of the histone acetylation changes. This corresponded with reduced astrocyte activation and an altered behavioral phenotype, which was characterized by high response to novelty. The diagnostic efficacy of epigenetic changes following blast was elucidated by the accumulation of cell-free nucleic acids in cerebrospinal fluid one month after injury. Concentrations of these molecules shows promise in discriminating between injured and non-injured individuals.
To date, the diagnostic and therapeutic efforts of BINT have been limited by the lack of a mechanistic understanding of the injury. This work provides novel diagnostic and therapeutic targets. The clinical potential impact on diagnosis and therapeutic intervention has been demonstrated. / Ph. D. / Blast-induced neurotrauma (BINT) is a prevalent brain injury within both military and civilian populations due to current engagement in overseas conflict and ongoing terrorist events worldwide. In the early 2000s, 78% of injuries were attributable to an explosive mechanism during overseas conflicts which has led to increased incidences of BINT [1a]. Clinical manifestations of BINT include long-term psychological impairments which are driven by the underlying cellular and molecular sequelae of the injury. To date, the development of effective treatment strategies has been unsuccessful. The work described herein seeks to evaluate the specific cellular mechanisms that contribute to the progression of the BINT pathology and neurological impairments. Epigenetic mechanisms are regulatory mechanisms that coordinate DNA modifications and DNA storage to facilitate altered cellular phenotypes. DNA modifications often involves DNA methylation, which is the addition of methyl groups to the DNA backbone. DNA storage is regulated by specific modifications to histone proteins. Histone acetylation is a well-studied modification process that is capable inciting either chromatin relaxation or compaction. Both DNA methylation and histone acetylation are important processes by which cells coordinate neurological and cellular response to environmental stimuli. To date, the role of epigenetics in BINT remains largely unknown.
An established rodent model of BINT was employed [3a]. Analysis of DNA methylation, which is involved in memory processes, showed decreased levels one week following injury which was accompanied by decreased expression of one of the enzymes responsible for facilitating the addition of methyl groups to DNA. The one week time point also showed dramatic decreases in histone acetylation which correlated to memory impairment. This change was observed in astrocytes which are support cells in the brain and are particularly vulnerable to blast-induced aberrations. Drug administration, targeting the histone acetylation equilibrium, successfully mitigated astrocyte activation and altered the behavioral phenotype.
Diagnosis of BINT remains clinically challenging. An accumulation of cell-free nucleic acids was observed the in cerebrospinal fluid one month after injury. Concentrations of these molecules shows promise in discriminating between injured and non-injured individuals. These nucleic acids are susceptible to DNA methylation and may provide a platform for studying epigenetic biomarkers.
To date, the diagnostic and therapeutic efforts of BINT have been limited by the lack of a mechanistic understanding of the injury. This work provides novel diagnostic and therapeutic targets. The potential clinical impact on diagnosis and therapeutic intervention has been demonstrated.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/78813 |
| Date | 06 September 2017 |
| Creators | Bailey, Zachary S. |
| Contributors | Biomedical Engineering, VandeVord, Pamela J., Xie, Hehuang David, Leung, Lai Yee, Lee, Yong Woo, Hall, Adam R. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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